Propofol (2,6-diisopropylphenol, formula I), is a short-acting hypnotic agent, effective for induction and maintenance of anesthesia (see, e.g., Rees et al., Annu. Rep. Med. Chem., 31, 41-50 (1996), and Trapani et al., Curr. Med. Chem., 7, 249 (2000)). Propofol also is used for intravenous (iv) sedation by target-controlled infusions (see, e.g., Leitch, Br. Dent. J., 194, 443 (2003)).

Induction of anesthesia with propofol is rapid, and maintenance can be achieved by continuous infusion or by intermittent bolus doses. Propofol is becoming the anesthetic of choice for ambulatory surgery in outpatients. Its greatest advantage is rapid recovery, even after long periods of anesthesia. A particularly low incidence of postoperative nausea and vomiting also has been observed. Disadvantages of propofol include a relatively high incidence of apnea, blood pressure reductions, and pain upon injection.
A large body of experimental evidence accumulated in the past decade demonstrates that the inhibitory central GABAergic neurotransmission represents an important target in mediating some of the pharmacological actions of propofol. GABA is the major inhibitory neurotransmitter in the vertebrate central nervous system (CNS), whose action is produced by its selective interaction with at least two classes of GABA receptors, namely GABAA and GABAB receptors. While GABAB receptors are members of the G-protein-linked receptor superfamily and are coupled with K+ and Ca+2  channels, GABAA receptors are an allosteric inhibitory neurotransmitter-gated ion channel coupled to an integral chloride channel (see, e.g., Sieghart, Pharmacol. Rev., 47, 181 (1995)). GABAA receptors are composed of a number of phylogenetically related subunits (α1-6, β1-4, γ1-3, δ, ε, ρ1-3), that coassemble to form a pentameric structure which contains a central Cl− channel. GABAA receptors express a complex pharmacology. It has been reported that a number of distinct classed of drugs (e.g., benzodiazepines and benzodiazepine-like compounds, beta-carbolines, steroids, barbiturates, alcohols, picrotoxin, and tert-butylbicyclophosphorothionate (TBOB) exert their effects by interacting with specific modulatory sites on this receptor (see, e.g., Barnard et al., Pharmacol Rev., 50, 291 (1998)). The effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons also have been reported (see, e.g., Eghbali et al., Eur. J. Pharmacol., 468(2), 75-82 (2003)). The extracellular domain of the GABAA receptor contains two GABA binding sites that, when occupied, induce channel opening and subsequent desensitization. The receptor also has binding sites for allosteric modulators, including some general anesthetics.
It has been observed that the action of general anesthetics may be mediated by a specific subunit of the GABAA receptor (see, e.g., Sanna et al., Mol. Pharmacol., 47, 213 (1995)). Indeed, propofol has been shown to produce a strong Cl− current activation at β1 homomeric receptors as well as at α1β1, α1β1γ2, and β1γ2 receptors. Propofol has been shown in electrophysiological assays to allosterically enhance the action of GABA at the GABAA receptor (see, e.g., Hales et al., Br. J. Pharmcol., 104, 619 (1991)), and also to prolong inhibitory postsynaptic currents mediated by GABAA receptors (see, e.g., Orser et al., J. Neurosci., 14, 7747 (1994)). Propofol can also open the GABAA receptor ion channel in the absence of GABA, although this usually occurs at higher concentrations of propofol than necessary to potentiate submaximal receptor response of GABA (see, e.g., Jones et al., J. Pharmacol. Exp. Ther., 274, 962 (1995)). It also has been observed that propofol and analogs thereof produced loss of righting reflex in tadpoles in the action at the GABAA α1β2γ2s receptor (see, e.g., Krasowski et al, J. Pharmacol. Exp. Ther., 297, 338 (2001)).
Recently, Patel et al., Br. J. of Pharm., 139, 1005 (2003) reported that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol, and that fatty acid amide hydrolase could be a novel target for anesthetic development.
Propofol does not bind at the GABA binding sites. It may bind in a crevice near the extracellular ends of the β subunit M2 and M3 membrane-spanning segments (see, e.g., Williams et al., J. Neurosci., 22, 7417 (2002)). The effects of propofol on channel kinetics suggest that it stabilizes as a double ligand, pre-open, nonconducting state (see, e.g., Bai et al., J. Neurosci., 19, 10635 (1999)). At low concentration (0.5 μM), propofol potentiates current induced by submaximal GABA concentrations but does not directly activate GABAA receptors. At 20-fold higher concentrations, propofol directly activates receptors, causing channel opening in the absence of GABA (see, e.g., Lam and Reynolds, Brain Res., 784, 178 (1998)).
Propofol has been used in the treatment of pathologies relating to the presence of free oxygen radicals (see, e.g., U.S. Pat. Nos. 5,308,874 and 5,461,080). Propofol has been shown to repair neural damage caused by free oxygen radicals in vitro (see, e.g., Sagara et al., J. Neurochem., 73, 2524 (1999) and Jevtovic-Todorovic et al., Brain Res., 913, 185 (2001)) and has been used in vivo to treat head injury (see, e.g., Kelly et al., J. of Neurosurgery, 90, 1042 (1999)).
There is evidence suggesting that propofol can protect endothelial cells against oxidative stress by inhibiting eNOS transcription and protein expression (see, e.g., Peng et al., Chin. Med. J. (Engl)., 116(5), 731-5 (2003)). Moreover, propofol enhances ischemic tolerance of middle-aged hearts, primarily by inhibiting lipid peroxidation (see, e.g., Xia et al., Cardiovasc. Res., 59, 113 (2003)).
The search for novel high-affinity ligands for the GABAA receptor has led to the synthesis of numerous propofol analogs, and to the determination of a structure-activity relationship of propofol binding affinity to GABAA (reviewed by, e.g., Trapani et al., Curr. Med. Chem., 7, 249 (2000)). The preparation of propofol analogs has been disclosed in, for example, Trapani et al., J. Med. Chem., 41, 1846 (1998).
It is possible to modify the molecular structure of propofol in order to optimize all its various activities (e.g., anesthetic, sedative, and anticonvulsant activities) or to yield drugs with more selective actions. Introduction of halogen or benzoyl substituents in the para position of the phenyl group of propofol yielded a series of molecules that inhibit the binding of t-[35S]butylbicylcophosphorothionate to GABAA receptors and potentiate GABA-evoked currents at these receptors with an efficacy similar to or higher than that of propofol (see, e.g., Trapani et al., supra).
The only recognized method for delivery of alkylphenols is by intravenous injection in a lipid-based emulsion. After iv administration, propofol is rapidly distributed from the blood into highly perfused areas such as heart, lung, and liver, and to tissues because of its high solubility in lipids. This high solubility enables propofol to cross the blood-brain barrier easily.
From a clinical viewpoint, several adverse effects have been found in patients undergoing treatment with propofol oil-emulsion. These include pain on injection, apnea, reduction in blood pressure, bradycardia, and excitatory events including convulsions (see, e.g., Langley et al., Drugs, 33, 334 (1988), Rees et al., Annu. Rep. Med. Chem., 31, 41 (1996), and Sneyd et al., J. R. Soc. Med., 85, 288 (1992)).
Recently, Bennett et al., Bioorg. Med. Chem. Lett., 13, 1971 (2003) disclosed the general anesthetic activity of a series of amino-2,6-dimethoxyphenyl ester derivatives. The new chemicals exhibit improved anesthetic activity in mice relative to propofol.
Therefore, there is a need for propofol analogs and methods for using propofol analogs to induce general anesthesia, a hypnotic effect, or sleep inducement in a subject. The invention provides such analogs and methods of use. Specifically, the invention provides propofol derivatives that can be used for anesthetic effect generally, and in small doses for hypnotic effect, sedation, or sleep inducement. The new compounds are substantially more active in inducing an anesthetic effect than propofol itself. The result of this increased activity means that the compounds can be used in larger doses for general anesthesia, but in smaller doses to induce a hypnotic effect, sedation, and sleep effect, thereby resulting in a reduction in propofol-related side effects (e.g., cardiovascular side effects). These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.